Fungal infections are probably the most common disorder of nails encountered in medical practice. It has been estimated that approximately 90% of elderly people have some degree of toenail involvement with fungi. Conditions of moisture and occlusion of the lower extremities favor fungal colonization. Pain may result from extreme deformity of the nail plate, but usually, the complaint is one of cosmetic appearance. The most common organisms involved in the fungal infections of the nail are Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Candida albicans, Microsporum persiccolor, Cephalosporium species, Aspergillus species, and Fusarium oxysporum. 
Fingernail infection is of far greater importance cosmetically and fortunately clears faster than toenail infection because of the more rapid growth rate of fingernails. Despite this, 4-6 months of oral griseofulvin may be required to bring about complete clearing of the fingernail. For toenail infections with extensive involvement of multiple digits, withholding treatment may be the best decision. One of the factors in the treatment decision is whether the patient is taking other medications, as griseofulvin interacts with several drugs, including anticoagulants.
Griseofulvin was the drug of choice for many years, but its low cure rate and the development of newer, more effective drugs has caused it to lose favor. Current therapeutic alternatives include itraconazole and terbinafine. These drugs are well tolerated, but attention to drug interactions is still necessary [Trepanier, E. F and Amsden, G. W. Annals of Pharmacotherapy, 32, 1998, 204-214].
At present, topical treatment of fungal infections directly to the nail plate is discouraging. Creams or solutions containing antifungal agents, such as imidazole derivatives, are able to deliver the active agent to the nail only for a short period of time and their permeability/penetration through the nail is very low.
U.S. Pat. No. 5,120,530 discloses an antimycotically-active nail varnish, containing an antimycotically-active substance (a morpholine derivative) and a water-insoluble film former which is a copolymerizate of acrylic acid esters and methacrylic acid esters having a low content of quaternary ammonium groups. The formulations disclosed are expected to be poorly effective because they do not contain a keratolytic agent or a humectant. As a result, the nail permeability and consequently the penetration of the antimycotic agent will be very low. In the present invention the humectant entraps the water in the film after evaporation of the organic solvents, thus enabling the solubilization of the active agents in the film. Because the water content of the nail is very low, the presence of water in the film should hydrate the nail and improve the transport of the active agents into the nail. The keratolytic agent should also help by increasing the penetration of the antifungal agent into the deeper layers of the nail.
U.S. Pat. No. 4,957,730 discloses a nail varnish comprising a water-insoluble film-forming substance and an antimycotic substance, specifically 1-hydroxy-2-pyridones. The formulations disclosed do not contain to a humectant. The nail permeability of the formulations disclosed and consequently the penetration of the active agent into the deeper layers of the nail is expected to be very low, thereby failing to achieve the desired pharmacological action and cure.
U.S. Pat. No. 5,814,305 discloses a nail preparation comprising an antifungal agent, at least one hydrophilic penetration agent, and a water-alcohol solvent medium. The formulations disclosed are disadvantageous; they are in the form of a lotion or fluid gel and do not contain a film-forming agent. As a result a sustained release action is not achieved with these formulations. The formulations disclosed are disadvantageous since such a dosage form would require multiple applications of the formulation, leading to poor patient compliance. Because of the hydrophilic character of the formulations, in the presence of water or mechanical contact, the lotion or gel will likely be washed off or removed from the nail, thereby reducing the accumulation of the active agents in the nail.
UK Patent Appl. No GB2202743 A discloses a topical antifungal composition in the form of a lotion, gel or varnish, comprising at least 1% by weight (relative to the total weight of the composition) of miconazole nitrate or econazole nitrate dissolved in a mixture of water, urea, and a water-soluble dissolving intermediary. Urea is used in the formulation as a solubility increasing agent. When the composition is in the form of a varnish it contains a resin. The lotion and gel formulations disclosed are disadvantageous since such a dosage form will not provide sustained release action and would require multiple applications of the formulation, leading to poor patient compliance. Because of the hydrophilic properties of the formulations, in the presence of water or mechanical contact, the lotion or gel will likely be washed off or removed from the nail, thereby reducing the accumulation of the active agents in the nail. The varnish formulations disclosed are disadvantageous, and do not contain a humectant. As a result, the antifungal agent will not be solubilized in the film, and the hydration of the nail and transport of the antifungal agent through the nail will be very low, preventing achievement of the desired pharmacological action. In addition, UK Patent Appl. No GB2202743 A describes a delivery system specific for miconazole nitrate or econazole nitrate, which is not therefore a general delivery system for other antifungal agents.
None of these prior art references suggest or disclose the use of a combination of antifungal agent, keratolytic agent, and a humectant (glycerol at high concentrations). This combination is particularly advantageous because it increases the penetration of the active antifungal agent through the nail and 10 thus provides better pharmacological action.
U.S. Pat. No. 5,346,692 discloses a nail lacquer for treating onychomycosis, which comprises (a) a film former agent, (b) at least one antimycotically active substance, (c) urea; and (d) a solvent which comprises (i) 50-70 wt. % of acetone; and (ii) 30-50 wt. % of 90 volume % aqueous ethanol. The formulations disclosed are disadvantageous since they use high concentrations of the antimycotically active substance and urea, thereby causing unwanted adverse effects (for example irritation and burning) which leads to poor compliance.
The formulations disclosed do not contain glycerol which would entrap the water in the film after evaporation of the organic solvents. The presence of water in the film enables the active agents to be maintained in a soluble form that is readily available for pharmacological action. Since the water content in the nail is very low, the presence of water in the film hydrates the nail so that the active agents can be delivered into deeper layers of the nail.
There is thus a need for, and it would be useful to have, a better formulation, containing low concentrations of the antifungal and keratolytic agents, to deliver pharmacologically active agents to the nail for the treatment of fungal infection thereof. This formulation would feature a film-forming agent and a humectant, for example, glycerol, for trapping water in the film formed on the nail, and the water so trapped would hydrate the nail for delivery of the agent thereto.
This formulation would be lower in cost because of the lower concentrations of the antifungal and keratolytic agents. Additionally, such formulation would reduce the unwanted side effects caused by high concentrations of the antifungal and keratolytic agents and yet be suitable for treatment of fungal infections of the nail and surrounding tissues.